Dale Schenk, Chief Scientific Officer, Discusses Alzheimer’s Disease Research Assertions
Recently, a paper published by Genentech scientists discussed new theories for Alzheimer’s disease therapies, and the pursuit of a new, potential “best-in-class” anti-beta amyloid (Aβ) antibody. Dale Schenk, Elan’s Chief Scientific Officer, discusses these assertions and describes Elan’s cutting-edge Alzheimer’s disease program.
Q: What is your opinion of the new theories regarding Aβ being discussed?
I say, “Not so fast.” Clearly, we believe in our science. Elan’s approach to Alzheimer’s disease is centered on research that clearly indicates that the accumulation of Aβ plaques in the brain is a hallmark pathology of Alzheimer’s disease. Elan and Wyeth have developed bapineuzumab, an experimental humanized monoclonal antibody designed to bind and clear beta amyloid in the brain. We are enrolling patients in Phase 3 clinical trials, and bapineuzumab has received fast track designation from the U.S. Food and Drug Administration.
The rationale for anti-Aβ immunotherapy for the treatment of Alzheimer’s disease is supported by numerous preclinical and clinical studies, and Elan has the leading patent estate around anti-Aβ antibodies.
Q: What are some of the strengths of bapineuzumab?
Bapineuzumab, which reacts with all toxic forms of Aβ, is the most advanced anti-Aβ antibody in clinical development. It is the only anti-Aβ antibody shown to have a positive impact on multiple aspects of AD-related pathology in animal studies. In these preclinical studies, it has been shown to bind to and clear Aβ plaques, bind to and neutralize neurotoxic Aβ oligomers and improve memory.
The Phase 2 bapineuzumab results showed trends toward improvement in the intent-to-treat population and by post hoc analyses, improvement in multiple endpoints. Bapineuzumab demonstrated acceptable safety and tolerability profile to advance to Phase 3.
Q: Isn’t it possible that there are viable alternative hypotheses?
We recognize that Alzheimer’s disease is complex, and know it is possible – and hopeful – that other targets might have therapeutic utility. For example, there is strong genetic and neuropathological data to support the idea that tau, like abeta, is also very much involved in Alzheimer’s disease.
In the recent paper published in Nature, Genentech scientists describe a previously unidentified pathway that appears to play a role in the normal developmental regulation of axon death. The published data suggest that a fragment of APP, termed N-APP, binds to the DR6 receptor on axons, initiating a signaling cascade that results in axonal death.
It is important to note, however, that APP is a large protein that, when processed, produces Aβ. Intense efforts during nearly two decades have never linked the secreted forms of APP directly with Alzheimer’s disease. And in hundreds of genes analyzed, the only ones that cause early onset forms of Alzheimer’s disease are those that increase Aβ42 production specifically: None of these mutations have been linked to N-APP.
While we find Genentech’s data on N-APP and DR6 interesting scientifically, it leaves a number of key questions unanswered, and it provides no preclinical or clinical validation for their hypothesis that these targets have therapeutic utility.
For example:
There is no evidence to show that the activity of APP/DR6 in normal early development has a role in patients suffering from Alzheimer’s disease.
The hypothesis is inconsistent with previously published mouse model data showing that secreted APP is, if anything, neurotrophic.
There is limited biochemical evidence in the Nature paper that the natural protein they identified is in fact N-APP.
With regard to Genentech’s claim that it may have a best in class anti-Aβ antibody in phase 1, we are aware of no published or public preclinical or clinical data to support their assertion.
Also, it will probably take many years, perhaps a decade, to move the APP/DR6 biological findings from the laboratory bench to clinical practice. In addition, like all new scientific findings, it will be important to see if the results are reproducible in other laboratories and relevant to the disease – as has been done for Aβ immunotherapy.
As the Genentech authors noted in Nature, “further study is required to determine the full implications of the APP–death-receptor mechanism in development, adult physiology and disease…”
I agree.
Elan is committed to being a leader in neuroscience and we believe that the successful development of our Alzheimer’s disease programs has the potential to help millions of Alzheimer’s patients, their families and their caregivers.